U.S. patent number 6,172,233 [Application Number 09/007,475] was granted by the patent office on 2001-01-09 for process for making paroxetine.
This patent grant is currently assigned to SmithKline Beecham plc. Invention is credited to Neal Ward.
United States Patent |
6,172,233 |
Ward |
January 9, 2001 |
Process for making paroxetine
Abstract
Compounds of structure (2) are prepared by reaction of an
arecoline analogue of structure(4) with an organometallic compound
containing an X-substituted phenyl group, such as a compound of
structure (3). ##STR1## Suitably the compound of structure (3) is a
Grignard reagent, where M is magnesium and Y is a halogen atom, or
M may be a Group II metal and Y is a halogen atom or a second
X-substituted phenyl group. When structure (3) is a Grignard
reagent, the reaction is carried out either in a suitable non-ether
solvent, typically a hydrocarbon or a non-reactive chlorinated
hydrocarbon, or in a mixture of such a solvent with diethyl ether.
Compounds of structure (2) are important intermediates in the
preparation of inter alia paroxetine.
Inventors: |
Ward; Neal (Tonbridge,
GB) |
Assignee: |
SmithKline Beecham plc
(Brentford, GB)
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Family
ID: |
10805974 |
Appl.
No.: |
09/007,475 |
Filed: |
January 15, 1998 |
Foreign Application Priority Data
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Jan 15, 1997 [GB] |
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9700690 |
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Current U.S.
Class: |
546/185; 546/227;
546/228 |
Current CPC
Class: |
C07D
211/22 (20130101); C07D 211/60 (20130101) |
Current International
Class: |
C07D
211/00 (20060101); C07D 211/22 (20060101); C07D
211/60 (20060101); C07D 211/02 (); C07D
211/60 () |
Field of
Search: |
;546/185,225,227,228 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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300617 |
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Jan 1989 |
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EP |
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374674 |
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Jun 1990 |
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EP |
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96/36636 |
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Nov 1996 |
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WO |
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Other References
Plati, et al., "Pyridindene Derivatives. III. Synthesis from
Arecoline", J. Org. Chem. 22, pp. 261-265 (Mar., 1957)..
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Primary Examiner: Kight; John
Assistant Examiner: Covington; Raymond
Attorney, Agent or Firm: Dustman; Wayne J.
Claims
What is claimed is:
1. A process for industrial scale preparation of a compound of
structure (2) ##STR7##
in which R and R' are independently selected from an alkyl, aryl,
or arylalkyl group, X is fluorine which comprises reacting a
compound of structure (4) ##STR8##
with an organometallic compound having one or more X-substituted
phenyl groups, in a suitable organic solvent, provided that the
solvent is not wholly an ether solvent when the organometallic
compound is a Grignard reagent.
2. A process according to claim 1, in which the organometallic
compound is a compound of structure (3) ##STR9##
in which X is as defined in claim 1, M is a Group II metal and Y is
a halogen or an X-substituted phenyl group.
3. A process according to claim 2, in which M is Zn and Y is a
second X-substituted phenyl group.
4. A process according to claim 2, in which structure (3) is a
Grignard reagent and the organic solvent is a non-ether solvent or
a mixture of a non-ether solvent with diethyl ether.
5. A process according to claim 4, in which M is Mg and Y is Cl or
Br.
6. A process according to claim 1, in which the solvent is a
hydrocarbon or a non-reactive chlorinated hydrocarbon.
7. A process for the preparation of a
4-aryl-3-hydroxymethyl-piperidine of structure (1) ##STR10##
comprising converting a compound of structure (2) obtained by the
process of claim 1 into a compound of structure (1).
8. A process for preparing paroxetine comprising obtaining a
compound of structure (1) in which X is 4-fluoro by a process as
claimed in claim 7, replacing the 3-hydroxymethyl group by a
3-(3,4-methylenedioxyphenyloxymethyl) group, and replacing the
substituent R with a hydrogen atom.
9. A process according to claim 8, in which paroxetine is obtained
as, or converted to, a hydrochloride salt.
10. A process according to claim 9, in which the paroxetine
hydrochloride salt is obtained as the hemihydrate.
11. Paroxetine when prepared according to the process of claim
8.
12. Paroxetine hydrochloride when prepared according to the process
of claim 9.
13. Paroxetine hydrochloride hemihydrate when prepared according to
the process of claim 10.
14. A process according to claim 1, in which the solvent contains
toluene.
15. A process according to claim 1, in which the solvent contains
dichloromethane.
16. A process according to claim 7, wherein a reducing agent is
used to convert the compound of structure (1) into a compound of
structure (2).
Description
The present invention relates to a new process for preparing
pharmaceutically active compounds and intermediates therefor.
Pharmaceutical products with antidepressant and anti-Parkinson
properties are described in U.S. Pat. No. 3,912,743 and U.S. Pat.
No. 4,007,196. An especially important compound among those
disclosed is paroxetine.
This invention aims to overcome disadvantages in the existing
processes for preparation of such compounds and so to provide
alternative processes for their manufacture.
This invention has been developed on the basis that compounds of
structure (1) and (2) below are valuable chemical intermediates
useful for the manufacture of important medicinal products, for
example paroxetine hydrochloride. ##STR2##
By reference to Example 4 of U.S. Pat. No. 4,007,196, paroxetine
may be prepared from a compound of structure (1) in which R is
methyl and X is 4-fluoro, that is
4-(4'-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine, by
replacing the hydroxymethyl group with
3,4-methylenedioxyphenoxymethyl, followed by demethylation,
replacing the R=methyl group by hydrogen. In the same Example,
4-(4'-fluorophenyl)-3-hydroxymethyl-1-methyl piperidine is prepared
by reduction of
4-(4'-fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6-tetrahydropyridine,
which is in turn prepared from
4-(4'-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine, by
reaction with formaldehyde.
U.S. Pat. No. 4,007,196 also discloses that compounds of structure
(1) which are 4-(fluorophenyl)-3-hydroxymethyl-1-alkyl piperidines
can be obtained by reduction of compounds of structure (2) which
are 4-(fluorophenyl)-3-carboxymethoxy-1-alkyl piperidines. The
latter are prepared using a literature procedure (J.T. Plati, A.K
Ingerman and W Wenner, Journal of Organic Chemistry (1957) Volume
22 pages 261-265). Plati et al describe the reaction of the
tetrahydropyridine arecoline with phenyl magnesium bromide in
diethyl ether to prepare 1-methyl-3-carbomethoxy-4-phenyl
piperidine (compound (2) where R and R' are methyl groups and X is
a hydrogen atom).
EP-A-0219034 discloses an alternative method for the preparation of
some 4-(substituted phenyl)-3-carboxyalkoxy-1-alkyl piperidines,
and their reduction to 4-(substituted
phenyl)-3-hydroxymethyl-1-alkyl piperidines.
Paroxetine is the (-) trans isomer of
4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy-phenoxymethyl)-piperidine.
The above described processes produce compounds of structure (1) as
a mixture of enantiomers. Therefore conversion of compounds of
structure (1) to useful pharmaceuticals will normally require a
resolution stage.
The Plati et al procedure uses diethyl ether, which is a very
flammable solvent and its use in large scale production is highly
undesirable. However, we have found that other ether solvents
conventionally used in Grignard reactions, such as tetrahydrofuran
or diisopropyl ether result in little if any of the desired
1,4-conjugate addition product, as the major product arises from
attack of the Grignard reagent on the ester grouping (so called
1,2-addition). We have also have found that the Plati procedure
generates thick unstirrable gels and is unsuitable for large scale
production of compounds of structure (2).
As a result, we have discovered that the Plati et al procedure used
in U.S. Pat. No. 4,007,196 can be improved by use of other
organometallic compounds in place of the Grignard reagent, or by
varying the conditions under which a Grignard reagent is used,
enabling the stirring problems to be overcome and the use of
diethyl ether eliminated or significantly reduced.
Accordingly a first aspect of this invention provides a process for
the preparation of a compound of structure (2) ##STR3##
in which R and R' are independently an alkyl, aryl, or arylalkyl
group, most suitably lower alkyl, and X is one or more of hydrogen,
halogen (especially fluoro), hydroxy, alkoxy, nitro, nitrile, amino
(optionally protected or substituted), trifluoromethyl, acyl,
formyl, carboxyl or carboxyalkyl, which comprises reacting a
compound of structure (4) ##STR4##
with an organometallic compound having one or more X-substituted
phenyl groups, in a suitable organic solvent, provided that the
solvent is not wholly diethyl ether when the organometallic
compound is a Grignard reagent.
The organometallic compound may be any X-substituted phenyl
derivative capable of undergoing a 1,4-conjugate to a compound of
structure (4), such as a Grignard reagent, and X-substituted phenyl
derivatives of Group II metals. For example, the organometallic
compound may be a compound of structure (3) ##STR5##
in which M is a Group II metal and Y is a halogen or an
X-substituted phenyl group. Suitable compounds of structure (3)
include Grignard reagents, in which case M is magnesium and Y is
conveniently chlorine or bromine. The compound of structure (3) may
also be a symmetrical molecule, where M represents for example a
zinc atom and Y is a second X-substituted phenyl group.
When structure (3) represents a Grignard reagent the reaction is
carried out either in a suitable non-ether solvent, or in a mixture
of such a solvent with diethyl ether. Suitable non-ether solvents
are those which are compatible with the reaction conditions for
example those which do not react with Grignard reagents. Such
solvents include hydrocarbons such as hexane or toluene, and
unreactive chlorinated hydrocarbons such as dichloromethane.
Where it is desired to carry out the reaction in a non-ether
solvent, the Grignard reagent of formula (3) may either be prepared
in the chosen solvent, or prepared in an ether solvent and the
ether subsequently removed by distillation and replaced by the
chosen solvent. When employed in a non-ether solvent, a Grignard
reagent of formula (3) may be partially or completely insoluble,
but the resulting suspension is stirrable and compatible with large
scale operation. When a mixture of diethyl ether and a suitable
non-ether solvent is employed, a completely clear solution may be
obtained, rendering the process particularly suitable for
industrial scale operation.
By using the processes of this invention the reaction has been
found to be more efficient, and the large excess of Grignard
reagent specified by Plati (2 molar equivalents) can be
significantly reduced without loss in yield. We have also found
that the reaction is equally efficient if the order of addition of
the reagents is reversed, i.e. the Grignard reagent is added to the
tetrahydropyridine ester.
Compounds of structure (3) may be prepared by conventional
procedures for Grignard reagents and the other organometallic
compounds, starting from an appropriately X-substituted aromatic
compound. Where the desired end product is paroxetine, an
appropriately X-substituted aromatic compound would be
1-bromo-4-fluorobenzene.
Compounds of formula (4) may be prepared from the natural products
guvacine, arecaidine or arecoline, by conventional methods, or by
synthesis from other materials. A particularly convenient synthetic
procedure involves the esterification, quaternisation and partial
reduction of nicotinic acid [see for example Journal of Organic
Chemistry (1955), volume 20, pages 1761-1765; Journal of Chemical
Research (1983), volume 10, pages 2326-2342; Journal of Ph
maceutical Sciences (1992), volume 81, pages 1015-1019; and
references quoted therein]. ##STR6##
Other methods for the preparation of compounds of structure (4) are
given in Tetrahedron (1989) volume 45 pages 23-258, and
Heterocycles (1990) volume 30 pages 885-896.
The compounds of structure (2) may be reduced to compounds of
structure (1) by the general procedures disclosed in
EP-A-0219934.
Compounds of structure (1) may be converted to an active compound
disclosed in U.S. Pat. No. 3,912,743 or U.S. Pat. No. 4,007,196
using conventional procedures disclosed therein. Where appropriate
or necessary, compounds of structure (1) may be resolved to obtain
the (-)trans isomer using conventional reagents such a nitro
tartranilic acid, as described in EP-A-0223334--see Example 5.
In particular, the compound of structure (1) in which X is 4-fluoro
may be used to prepare paroxetine. The paroxetine is preferably
obtained as the hydrochloride salt and most preferably as the
hemihydrate of that salt, as described in EP-A-0223403.
The present invention includes within its scope the compound
paroxetine, particularly paroxetine hydrochloride, especially as
the hemihydrate, when obtained via any aspect of this invention,
and any novel intermediates resulting from the described
procedures.
The invention is illustrated by the following Examples:
Example 1
1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine
A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl
ether (5 ml, 2 molar equivalents) was diluted with toluene (5 ml)
and heated under nitrogen until the ether had been removed. The
resulting suspension was cooled to ca. -5.degree. C. and treated
with a solution of arecoline (0.78 g) in toluene (4.5 ml) over 15
minutes. The mixture was stirred at -5.degree. C. for 1 hour, then
quenched by the addition of a mixture of water (25 ml) and
concentrated hydrochloric acid (3 ml). Analysis of the aqueous
phase by HPLC showed that yield of cis/trans
1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 880
mg (70 %).
Example 2
1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine
A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl
ether (5 ml, 2 molar equivalents) was stirred at -5 to -10.degree.
C. under nitrogen, and a solution of arecoline (0.78 g) in toluene
(5.0 ml) added over 15 minutes at -5.degree. C. The clear solution
was stirred at -5.degree. C. for 1 hour, then quenched by the
addition of a mixture of water (25 ml) and concentrated
hydrochloric acid (3 ml). Analysis of the aqueous phase by HPLC
showed that yield of cis/trans
1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 905
mg (72 %).
Example 3
1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine
A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl
ether (5 ml, 2 molar equivalents) was stirred at -5 to -10.degree.
C. under nitrogen, and a solution of arecoline (0.78 g) in
dichloromethane (4.0 ml) added over 15 minutes at -5.degree. C. The
clear solution was stirred at -5.degree. C. for 1 hour, then
quenched by the addition of a mixture of water (25 ml) and
concentrated hydrochloric acid (3 ml). Analysis of the aqueous
phase by HPLC showed that yield of cis/trans
1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 950
mg (76 %).
Example 4
1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine
A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl
ether (3.5 ml, 1.4 molar equivalents) was stirred at -5 to
-10.degree. C. under nitrogen, and a solution of arecoline (0.78 g)
in dichloromethane (4.0 ml) added over 15 minutes at -5.degree. C.
The clear solution was stirred at -5.degree. C. for 1 hour, then
quenched by the addition of a mixture of water (25 ml) and
concentrated hydrochloric acid (3 ml). Analysis of the aqueous
phase by HPLC showed that yield of cis/trans 1
ethyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 965 mg
(77 %).
Example 5
1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine - reverse
addition
A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl
ether (3.5 ml, 1.4 molar equivalents) was added over 15 minutes to
a stirred solution of arecoline (0.78 g) in dichloromethane (4.0
ml) at -5 to -10.degree. C. under nitrogen. The clear solution was
stirred at -5.degree. C. for 1 hour, then quenched by the addition
of a mixture of water (25 ml) and concentrated hydrochloric acid (3
ml). Analysis of the aqueous phase by HPLC showed that yield of
cis/trans 1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was
about 970 mg (77 %)
* * * * *